Naratriptan belongs to a family of tryptamine based drugs (triptans) used as selective (1B/1D) serotonin 5-hydroxytryptamine (5-HT) agonists. It is used in the treatment of migraine and cluster headaches. Its action is attributed to its binding to serotonin 5-HT1B and 5-BT1D receptors in cranial blood vessels (causing their constriction) and subsequent inhibition of pro-inflammatory neuropeptide release. It acts on serotonin receptors in nerve endings as well as the blood vessels. This leads to a decrease in the release of several peptides, including CGRP and substance P.

U.S. Pat. No. 4,997,841 discloses naratriptan, its salts and several processes for its preparation. One of the processes comprises reacting 5-bromoindole with 1-methylpiperidin-4-one by means of KOH in methanol at room temperature to give 5-bromo-3-(4-(hydroxy-1-methylpiperidin-4-yl)-1H-indole, which is condensed with N-methylvinylsulfonamide by means of palladium acetate and tri-p-tolyl phosphine in hot DMF to afford (E)-N-methyl-2-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]vinylsulfonamide. Finally, this compound is hydrogenated with H2 over Pd/C to obtain naratriptan.
In another process as described in US '841, if the reaction of 5-bromoindole with 1-methylpiperidin-4-one by means of KOH in methanol is carried out at reflux temperature the resulting product is 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole which is further condensed with N-methylvinylsulfonamide as described above to obtain naratriptan.
Another process disclosed in US '841 comprises cyclization of 2-(4-hydrazinophenyl)-N-methylethanesulfonamide with 2-(1-methylpiperidin-4-yl)acetaldehyde by means of HCl in water.
U.S. Pat. No. 5,786,473 describes a reaction of 5-bromoindole with N-methyl-4-piperidone to obtain 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole which is condensed with N-methylvinylsulfonamide to afford N-methyl-2-[3-(1,2,3,6-tertahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulfonamide which is reduced under heterogeneous hydrogenation conditions to obtain naratritpan.
WO2006010079 discloses the preparation of naratriptan based on the Japp-Klingemann reaction as a key step in building the indole moiety. The process comprises diazotizing N-methyl-2-(4-aminophenyl)-ethane sulfonamide with methyl-2-acetyl-3-pyridyl propanoate under Japp-Klingemann coupling to afford the corresponding hydrazone compound which is cyclised in the presence of an acid to afford methyl-5-methyl sulfamoylethyl-3-(4-pyridyl)-1H-2-indole carboxylate. It is quaternized using methyl iodide to obtain 1-methyl-4-(2-methoxy carbonyl-5-methyl sulfamoylethyl-1H-3-indolyl)pyridinium iodide followed by the further steps of reduction, saponification and decarboxylation to obtain naratriptan.
WO2008072257 teaches a process for the preparation of naratriptan comprising cyclizing 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester to form 5-(2-methyl sulfamoyl-ethyl)-1-H-indole-2-carboxylic acid ethyl ester which is hydrolyzed to form 5-(2-methyl sulfamoyl-ethyl)-1-H-indole-2-carboxylic acid, followed by decarboxylation to obtain 5-(2-methyl sulfamoyl-ethyl)-1-H-indole. Further, this compound is condensed with N-methyl-4-piperidone to obtain 2-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole-5yl]ethanesulfonic acid methyl amide followed by reduction to obtain naratriptan.
Naratriptan is a highly potent anti-migraine agent and there is a constant need for simpler and more industrially-applicable processes for its preparation. The inventors of the present invention aimed to develop such a process.